Pain is an intractable disease which reduces the QOL (Quality of Life) of the affected individuals. The number of chronic pain sufferers in the world is reported to exceed 20 million, and the combined market size of Japan, the U.S. and Europe for pain medicines is said to be about 2 trillion yen. In addition, the number of patients with diseases which may be a cause of pain, such as stroke, cancer, diabetes and viral infection, has been increasing, and under such circumstances, the establishment of an appropriate treatment modality for pain is a very important medical issue. Particularly, neuropathic pain is less sensitive to nonsteroidal antiinflammatory drugs and opioid analgesics, and is a disease with significant unmet medical needs. However, the pathogenesis of neuropathic pain is diverse and the underlying molecular mechanism is very complicated. Therefore, radical therapeutic medicines for neuropathic pain are yet to be developed (Non Patent Literature 1). Clarifying the molecular mechanism of the development and maintenance of neuropathic pain leads to the development of breakthrough medicines and is expected to provide a promising solution to one of the biggest medical issues in the 21st century.
The dorsal horn of the spinal cord is considered to be one of the major causative site of neuropathic pain (Non Patent Literature 2). Peripheral sensory inputs undergo various processing, such as amplification, attenuation and integration, in the dorsal horn of the spinal cord, and are transmitted to the brain. However, injury of peripheral nerves reportedly induces neural network changes in the dorsal horn of the spinal cord, for example abnormal axon collateral formation and enhanced synaptic transmission, thus triggering pain (Non Patent Literature 3). Therefore, clarifying a novel molecular mechanism which regulates the neural circuit in the dorsal horn of the spinal cord is expected to lead to the discovery of a novel target molecule required for the development of breakthrough medicines for pain.
FLRT3 (fibronectin and leucine-rich transmembrane protein-3) is a member of the fibronectin leucine-rich repeat transmembrane protein family and has a FN (fibronectin) type III domain and leucine-rich repeats. FLRT3 is expressed in various tissues including kidney, skeletal muscle, brain and lung (Non Patent Literature 4). FLRT3 is reported to play important roles in the cell and tissue morphogenesis during early embryogenesis, including neurite formation (Non Patent Literature 5), cell adhesion (Non Patent Literature 6), axon guidance (Non Patent Literature 7), etc. Also reported is that, after peripheral nerve injury, FLRT3 protein expression increases at the axon terminals of dorsal root ganglion neurons projecting into the dorsal horn of the spinal cord (Non Patent Literature 8). Moreover, FLRT3 is reported to bind to the Unc5B receptor (Non Patent Literature 7 and 9). However, there have been no study reports on the in vivo functions of FLRT3 in the adult spinal cord, and it has yet to be clarified whether FLRT3 is involved in the development of neuropathic pain.